Insights into the Binding Mode of Lipid A to the Anti-lipopolysaccharide Factor ALFPm3 from Penaeus monodon: An In Silico Study through MD Simulations

The globally expanding threat of antibiotic resistance calls for the development of new strategies for abating Gram-negative bacterial infections. The use of extracorporeal blood cleansing devices with affinity sorbents to selectively capture bacterial lipopolysaccharide (LPS), which is the major co...

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Autores: González-Fernández, Cristina, Öhlknecht, Christoph, Diem, Matthias, Escalona, Yerko, Bringas, Eugenio, Moncalián, Gabriel, Oostenbrink, Chris, Ortiz, Inmaculada
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/339413
Acceso en línea:http://hdl.handle.net/10261/339413
Access Level:acceso abierto
Palabra clave:Cavities
Lipids
Monomers
Peptides and proteins
Screening assays
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spelling Insights into the Binding Mode of Lipid A to the Anti-lipopolysaccharide Factor ALFPm3 from Penaeus monodon: An In Silico Study through MD SimulationsGonzález-Fernández, CristinaÖhlknecht, ChristophDiem, MatthiasEscalona, YerkoBringas, EugenioMoncalián, GabrielOostenbrink, ChrisOrtiz, InmaculadaCavitiesLipidsMonomersPeptides and proteinsScreening assaysThe globally expanding threat of antibiotic resistance calls for the development of new strategies for abating Gram-negative bacterial infections. The use of extracorporeal blood cleansing devices with affinity sorbents to selectively capture bacterial lipopolysaccharide (LPS), which is the major constituent of Gram-negative bacterial outer membranes and the responsible agent for eliciting an exacerbated innate immune response in the host during infection, has received outstanding interest. For that purpose, molecules that bind tightly to LPS are required to functionalize the affinity sorbents. Particularly, anti-LPS factors (ALFs) are promising LPS-sequestrating molecules. Hence, in this work, molecular dynamics (MD) simulations are used to investigate the interaction mechanism and binding pose of the ALF isoform 3 from Penaeus monodon (ALFPm3), which is referred to as “AL3” for the sake of simplicity, and lipid A (LA, the component of LPS that represents its endotoxic principle). We concluded that hydrophobic interactions are responsible for AL3–LA binding and that LA binds to AL3 within the protein cavity, where it buries its aliphatic tails, whereas the negatively charged phosphate groups are exposed to the medium. AL3 residues that are key for its interaction with LA were identified, and their conservation in other ALFs (specifically Lys39 and Tyr49) was also analyzed. Additionally, based on the MD-derived results, we provide a picture of the possible AL3–LA interaction mechanism. Finally, an in vitro validation of the in silico predictions was performed. Overall, the insights gained from this work can guide the design of novel therapeutics for treating sepsis, since they may be significantly valuable for designing LPS-sequestrating molecules that could functionalize affinity sorbents to be used for extracorporeal blood detoxification.Financial support from the Spanish Ministry of Science, Innovation and Universities under the project RTI2018-093310-B-I00 is gratefully acknowledged. C.G.F. also thanks the Spanish Ministry of Universities for the Margarita Salas postdoctoral fellowship (grants for the requalification of the Spanish university system for 2021–2023, University of Cantabria), funded by the European Union-NextGenerationEU.American Chemical SocietyMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Ministerio de Universidades (España)Universidad de CantabriaEuropean CommissionConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2023202320232023info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/339413reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-093310-B-I00González-Fernández, Cristina; Öhlknecht, Christoph; Diem, Matthias; Escalona, Yerko; Bringas, Eugenio; Moncalián, Gabriel; Oostenbrink, Chris; Ortiz, Inmaculada; 2023; Insights into the Binding Mode of Lipid A to the Anti-lipopolysaccharide Factor ALFPm3 from Penaeus monodon: An In Silico Study through MD Simulations [Dataset]; American Chemical Society; https://doi.org/10.1021/acs.jcim.3c00173.s001http://dx.doi.org/10.1021/acs.jcim.3c00173Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3394132026-05-22T06:33:51Z
dc.title.none.fl_str_mv Insights into the Binding Mode of Lipid A to the Anti-lipopolysaccharide Factor ALFPm3 from Penaeus monodon: An In Silico Study through MD Simulations
title Insights into the Binding Mode of Lipid A to the Anti-lipopolysaccharide Factor ALFPm3 from Penaeus monodon: An In Silico Study through MD Simulations
spellingShingle Insights into the Binding Mode of Lipid A to the Anti-lipopolysaccharide Factor ALFPm3 from Penaeus monodon: An In Silico Study through MD Simulations
González-Fernández, Cristina
Cavities
Lipids
Monomers
Peptides and proteins
Screening assays
title_short Insights into the Binding Mode of Lipid A to the Anti-lipopolysaccharide Factor ALFPm3 from Penaeus monodon: An In Silico Study through MD Simulations
title_full Insights into the Binding Mode of Lipid A to the Anti-lipopolysaccharide Factor ALFPm3 from Penaeus monodon: An In Silico Study through MD Simulations
title_fullStr Insights into the Binding Mode of Lipid A to the Anti-lipopolysaccharide Factor ALFPm3 from Penaeus monodon: An In Silico Study through MD Simulations
title_full_unstemmed Insights into the Binding Mode of Lipid A to the Anti-lipopolysaccharide Factor ALFPm3 from Penaeus monodon: An In Silico Study through MD Simulations
title_sort Insights into the Binding Mode of Lipid A to the Anti-lipopolysaccharide Factor ALFPm3 from Penaeus monodon: An In Silico Study through MD Simulations
dc.creator.none.fl_str_mv González-Fernández, Cristina
Öhlknecht, Christoph
Diem, Matthias
Escalona, Yerko
Bringas, Eugenio
Moncalián, Gabriel
Oostenbrink, Chris
Ortiz, Inmaculada
author González-Fernández, Cristina
author_facet González-Fernández, Cristina
Öhlknecht, Christoph
Diem, Matthias
Escalona, Yerko
Bringas, Eugenio
Moncalián, Gabriel
Oostenbrink, Chris
Ortiz, Inmaculada
author_role author
author2 Öhlknecht, Christoph
Diem, Matthias
Escalona, Yerko
Bringas, Eugenio
Moncalián, Gabriel
Oostenbrink, Chris
Ortiz, Inmaculada
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
Ministerio de Universidades (España)
Universidad de Cantabria
European Commission
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Cavities
Lipids
Monomers
Peptides and proteins
Screening assays
topic Cavities
Lipids
Monomers
Peptides and proteins
Screening assays
description The globally expanding threat of antibiotic resistance calls for the development of new strategies for abating Gram-negative bacterial infections. The use of extracorporeal blood cleansing devices with affinity sorbents to selectively capture bacterial lipopolysaccharide (LPS), which is the major constituent of Gram-negative bacterial outer membranes and the responsible agent for eliciting an exacerbated innate immune response in the host during infection, has received outstanding interest. For that purpose, molecules that bind tightly to LPS are required to functionalize the affinity sorbents. Particularly, anti-LPS factors (ALFs) are promising LPS-sequestrating molecules. Hence, in this work, molecular dynamics (MD) simulations are used to investigate the interaction mechanism and binding pose of the ALF isoform 3 from Penaeus monodon (ALFPm3), which is referred to as “AL3” for the sake of simplicity, and lipid A (LA, the component of LPS that represents its endotoxic principle). We concluded that hydrophobic interactions are responsible for AL3–LA binding and that LA binds to AL3 within the protein cavity, where it buries its aliphatic tails, whereas the negatively charged phosphate groups are exposed to the medium. AL3 residues that are key for its interaction with LA were identified, and their conservation in other ALFs (specifically Lys39 and Tyr49) was also analyzed. Additionally, based on the MD-derived results, we provide a picture of the possible AL3–LA interaction mechanism. Finally, an in vitro validation of the in silico predictions was performed. Overall, the insights gained from this work can guide the design of novel therapeutics for treating sepsis, since they may be significantly valuable for designing LPS-sequestrating molecules that could functionalize affinity sorbents to be used for extracorporeal blood detoxification.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/339413
url http://hdl.handle.net/10261/339413
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-093310-B-I00
González-Fernández, Cristina; Öhlknecht, Christoph; Diem, Matthias; Escalona, Yerko; Bringas, Eugenio; Moncalián, Gabriel; Oostenbrink, Chris; Ortiz, Inmaculada; 2023; Insights into the Binding Mode of Lipid A to the Anti-lipopolysaccharide Factor ALFPm3 from Penaeus monodon: An In Silico Study through MD Simulations [Dataset]; American Chemical Society; https://doi.org/10.1021/acs.jcim.3c00173.s001
http://dx.doi.org/10.1021/acs.jcim.3c00173
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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